Basic esters of aliphatic tertiary carboxylic acids



Patented Jan. 25, 1949 ITED STATES PATENT BASIC ESTERS OF ALIPHATIC TERTIARY CARBOXYEIC ACIDS Henry Martin and Alfred Margot, Basel, Switzerland, assignors'to J; R. Geigy A. G., Basel, Switzerland, a- Swiss firm NoDrawingu ApplicatiomAugustld,1944, Serial No. 549,492. lnswitzerlandiAugust l, 1943 Claims.

phenyl acetic acids and of their hydrogenation products, have become known as compounds having neurotropic, atropine-like properties.

According toexperirnents of Fromherz and of other authors (cf. Arch. exp. Path. u. Pharm.

R, R and R meaning the same or difierent saturated or unsaturated alkyl radicals.

173, 124 (1933)) basic esters of aliphatic carboxylic acids do not possess antispasmodic effects in any great extent. The aliphatic carboxylic acid esters known by the patent literature, such as the isovaleric acid ester, the a-bromoisovaleric acid ester, the isopro-pylallyl acetic acidesteiythe diethyl. acetic acid ester of the 3-diethylamino- 2:2 dimethyl l propanol, also show only a. very small neurotropic-atropine-like behaviour. Moreover, the esters mentioned by Halpern (of; Arch. internat. de Pharmacodyn, 59, 149 (1938)), such as the ethylbutyl acetic acid ester or the dibutyl acetic acid ester of diethylaminoethanol, the dibutyl acetic acid ester. of diethylamino-(1)- propanol-(3), the acetic acid ester, propionic acid ester, n-butyric acid ester,diethyl' acetic acid ester, ethylbutyl acetic acid ester or the dibutyl acetic acid ester of diethylamino-(l)-pentanol- (4) do not have much better efiects.

Ithas now been found that the basic esters ofaliphatic tertiary carboxylic acids possess a manifest neurotropic, atropine-like efficacy and, in addition, besides good. papaverine-like properties. When applying these products the mostly undesired icy-effects of atropine are largely diminished or even avoided;

For the preparation of the esters for instance The tertiary trialkyl acetic acids which are used as starting material may be obtained by alkylating the nitrilesof monoor dialkyl acetonit'riles in the-presence of sodium amide according toZiegler, Annalen der Chemie, vol. 495, page 84- or German Patent 570,59i and subsequent hydrolysis of the so-obtained nitriles with an alcoholic solution of sodium or potassium hydroxide at temperatures ranging up to 180 C.

Reactive esters of amino alcohols falling within thescope of the invention are especially esters withv hydrogen halide acids, with aryl sulfonic acids and the like.

A further object of the invention consists in converting aliphatic tertiary carboxylic acids reactive derivatives of the. aliphatic: tertiary carboxylic acids, i. e. their halides, esters:v or

anhydrides, are causedlto: react: in the. presence;

or: absence; of condens ation, agents with. tertiarily substituted amino alcohols or reactive esters of R\ H.011, R-0.0.Q OH and. 0.00011.

into their halogen alkyl esters and in causing the latter to react with secondary amines. For the preparation of halogen alkyl esters, it is advantageous to react alkylene halogen hydrines withaliphatic tertiary carboxylic acids or with their halides, esters or anhydrides in the presence or absence of condensation agents or to react alkylene halogen hydrines or alkylene dihalides with salts of the said acids, the hydroxyl groups which may be present in the so-obtained compounds being subsequently replaced by halogen.

The. basic esters claimed herein are colorless oils which, in form of their salts with inorganic or'organic acids, are soluble in water.

'I'hepresent invention will now be illustrated byway of. the following examples, the parts being by weight, unless otherwise stated.

Example 1 9=parts of methyl-di-n-propyl acetic acid chloride areadded, while stirring, to 6 parts of diethyl-amino ethanol and the mixture is heated, under stirring, for a short time to C. Theclear; yellowish-brown solution is treated, advantageously still Warm, with water and the aqueous. solution is extracted several times with.

ether. Then the base is freed by means of concentratedammonia and extracted with ether. After having once washed the ethereal solution with water and then having dried the same, the

solvent is distilled oil. The. residue boils. at.

133 to.1;86 C. when distilled at a pressure of 11 mm.

When using, instead of the diethylamino eth- 3 anol, other basic alcohols, for instance the following esters having the boiling points mentioned below are obtained:

The piperidino ethanol ester of methyl-di-npropyl acetic acid forms a hydrochloride of the melting point of 153-155 C.

Example 2 16 parts of methyl ethyl-n-butyl acetic acid are heated for 24 hours to boiling, while stirring, with 14 parts of ,8-chloroethyl diethylamine and with 20 parts of potassium carbonate in 250 parts by volume of dry acetic acid ester. After cooling the potassium chloride is filtered by suction, the residue is washed with acetic acid ester and the combined acetic acid ester solutions are treated with dilute hydrochloric acid. The resulting acid solution is extracted with ether, then the base is freed by addition of a potassium carbonate solution and extracted with ether. After drying of the etheral solution the solvent is distilled off. The residue boils at 11 mm. pressure at 137-139 C. v

In an analogous manner for instance the following esters are obtained with the correspond- Example 3 35 parts of diethyl-n-butyl acetic acid chloride are caused to react in the presence of pyridine with 1'7 parts of ethylene chlorohydrine. After complete reaction the mixture is extracted with ether and water, the ethereal solution is dried and the solvent distilled off. The residue is fractionated in vacuo and 20 parts of the so-obtained diethyl-n-butyl acetic acid-c-chloroethyl ester are interacted in the heat with 14 parts of piperidine. The mixture is extracted with ether and water. After having dried the ethereal solution the solvent is distilled off. The residue boils at 11 mm. pressure at 146149 C.

When using the corresponding acid chlorides, there may be obtained for instance the following esters:

Example 4- 10 parts of methyl-di-isobutyl acetic acid chloride are brought to interaction with 5 parts of dimethylamino propanol and worked up in the manner described in Example 1. Thus the dimethylaminopropanol ester of the methyl-di-isobutyl acetic acid is obtained in form of a colorless oil having the boiling point at 13 mm. pressure of 146-149 C.

When using methyl-n-propyl-n-butyl acetic acid chloride and diethylamino propanol, there will be obtained in an analogous manner the corresponding ester boiling at 12 mm. pressure at 160-162; from methyl ethyl-n-butyl acetic acid chloride and m-methylethylamino cyclohexanol the corresponding ester of the boiling point at 0.1 mm. pressure of 162-165 C. is obtained, while by interaction of ethylidene-n-butyl acetic acid chloride and dimethyl amino propane] the corresponding ester boiling at 11 mm. pressure at 138140 C. will be produced.

What we claim is:

1. A basic ester of an aliphatic tertiary carboxylic acid, of the formula wherein A1 and A2 each represents a lower alkyl group and A1 and A2 together contain from 5 to 8 carbon atoms, X represents a divalent radical selected from the group consisting of -CH2.CH2--, CH2.CH2.CH2 and radicals, and Am stands for the radical of a secondary amine selected from the group consisting of lower dialkyl amines and piperidine.

2. A basic ester of an aliphatic tertiary carb'oxylic acid, of the formula A1 Az-('1OO-OXAni wherein A1 represents an alkyl radical containing at least 3 and at most 5 carbon atoms, A2 represents an alkyl radical containing at least 2 carbon atoms, and A1 and A2 together contain from 5 to 8 carbon atoms, X represents a divalent radical selected from the group consisting of -CH2.CH2, CH2.CH2.CH2 and CHz-CH:

--CH CH: oH,( 3

radicals, and Am stands for the radical of a secondary amine selected from the group consisting of lower dialkyl amines and piperidine.

3. The piperidinoethanol ester of methyl-di-npropyl acetic acid of the formula being a. colorless oil of the boiling point of 157 C. at 11 mm. pressure and forming a hydro- 5 chloride of the melting point of 153-l55 C., possessing valuable therapeutic properties.

4. The dimethylaminopropanol ester of methyl-di-isobutyl acetic acid of the formula being a. colorless oil of the boiling point of 146- 149 C. at 13 mm. pressure, possessing valuable therapeutic properties.

5. The diethylaminoethanolester of methyl-npropyl-n-butyl acetic acid of the formula being a colorless oil of the boiling point of 147- 148 C. at 12 mm. pressure, possessing valuable therapeutic roperties.

HENRY MARTIN, ALFRED MARGOT.

REFERENCES CITED The following references are of record in the o file of this patent:

UNITED STATES PATENTS Name Date Bohm Nov. 26, 1940 OTHER REFERENCES Gilman et al., Jour. of Pharmacology & Experimental Therapeutics, March 1942.

Arch. Int. de Pharmacodyn, et de Therapie, vol. 59,-pp. 149-151 (1938).

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